Traditionally, hyperthermia has been used in conjunction with radiation therapy in an attempt to improve local tumor control. Previous use of dogs in this program have addressed this combination and useful information regarding thermal dosimetry and tumor response has been generated. In this project we are proposing to continue the previously- initiated phase III thermal dose trial for one year to develop an adequate level of statistical confidence in the conclusions of the trial However, the majority of work in this project involves a shift in the emphasis on hyperthermia use to: 1) enhance delivery and release of liposomally- encapsulated doxorubicin and 2) indue intratumoral production of cytokines by the heat shock response. These exciting new approaches to the use of hyperthermia have great potential to enhance therapy of human cancer and will expand the role of hyperthermia in the medical community. First, the toxicity of hyperthermia and a new thermosensitive doxorubicin-containing liposome will be assessed in a dose-seeking study in dogs with spontaneous tumors. Once the maximally tolerated dose (MTD) is identified, the efficacy of this combination will be tested with local hyperthermia and radiation in dogs with soft tissue sarcomas. Tumor control will be compared to historical data from prior trials of hyperthermia and radiation in dogs with soft tissue sarcomas. It is anticipated that sufficient local control will be observed to justify taking this agent into phase III trials in humans. The second major thrust of this project will be assessment of the toxicity of adenoviral-mediated, heat- induced gene therapy resulting in intratumoral induction of IL-12. This will be done via a dose-seeking study, where adenoviral vector is the dose, in cats with soft tissue sarcomas. Once the MTD of adenovirus, or the dose resulting in production of a targeted level of IL-12, is reached, a phase II study will be initiated in cats with soft tissue sarcomas. Cats will receive radiation therapy, a phase II study will be initiated in cats with soft tissue sarcoma. Cats will receive radiation therapy, followed by hyperthermia and adenovirus, with subsequent surgical removal of the tumor and assessment of metastasis. Results will be compared to historical controls of cats treated with surgery and radiation. It is expected that adequate local control will be observed to initiate phase III trials of this new approach in humans. These studies take advantage of the ability to administer novel therapies in a spontaneous tumor model. Rapid acquisition of information from this model will decrease the time required to formulate an opinion about such therapies can be applied to human.